Granulomatosis with polyangiitis

Synonym: Klinger's syndrome; Wegener's granulomatosis

What is granulomatosis with polyangiitis?

Granulomatosis with polyangiitis (GPA) - formerly known as Wegener's granulomatosis - is a rare form of vasculitis.¹ Granulomatosis with polyangiitis It is thought to be an autoimmune inflammatory process affecting endothelial cells. It is a multisystem disease which can affect many parts of the body, categorised by the ELK classification: it most commonly presents with lesions in the upper respiratory tract (E indicating ears/nose/throat, almost 100%), lungs (L most patients) and kidneys (K >75%). Many other areas of the body may also be affected, with joint inflammation occurring in 25-50% of all cases. The sinuses, eyes and skin may also be affected.^{2 3 4}

Granulomatosis with polyangiitis epidemiology

• A study using information from the UK General Practice Research Database reported an overall annual incidence of 8.4/million.⁵

• One study looking at GPA as a cause of renal vasculitis showed that the annual incidence of such cases in the UK was 5.8/million. The incidence was found to be lower in Japan.⁶

• The male:female ratio is approximately1.2:1.⁵

• The condition can occur at any age but peaks between the ages of 35-55. One American study found that the incidence in children was increasing.⁷

• Another study found that first-degree relatives had a moderately increased risk of developing any autoimmune/inflammatory disease, including specific associations with, for example, multiple sclerosis, Sjögren's syndrome and seropositive rheumatoid arthritis.⁸

Granulomatosis with polyangiitis risk factors

The higher incidence in winter suggests an infective aetiology but the data are inconclusive. GPA has been linked to parvovirus and to chronic nasal carriage of Staphylococcus aureus.

The involvement of the upper airways in this condition has led to the search for possible inhaled allergens, although none has yet been positively identified.⁹

Granulomatosis with polyangiitis symptoms^{10 11}

As a multisystem disease, GPA often presents with nonspecific symptoms and can be difficult to recognise in primary care. The delay from onset to diagnosis ranges from 2-20 months.¹²

GPA symptoms

Symptoms may include:

• Fatigue, malaise.

• Fever, night sweats.

• Weakness.

• Loss of appetite.

• Weight loss.

• Rhinorrhoea.

• Sinusitis.

• Facial pain.

• Hoarseness.

• Cough.

• Dyspnoea.

• Wheezing.

• Chest pain.

• Joint pains.

• Hearing loss.

• Abdominal pain, nausea and vomiting, GI bleeding. ¹³¹⁴

In children the renal and respiratory systems are most commonly affected.¹⁵

Signs of GPA

The signs found in granulomatosis with polyangiitis occur as a result of the inflammation of the small vessels and may affect any part of the body.

The most commonly seen signs relate to the upper and lower airways and the renal tract and may include:

• Ulcers, sores and crusting, in and around the nose, with destruction of nasal cartilage.

• Rhinorrhoea, often bloody.

• Haemoptysis.

• Haematuria.

• Subglottic stenosis (38% in one study) - causing hoarseness, stridor, dyspnoea, or cough.¹⁶

• Rashes (up to 50%) - often small red/purple raised areas or blister-like lesions, ulcers or nodules.¹¹

• Conjunctivitis, scleritis and episcleritis (32%).¹⁷

• Chronic ear infections.

• Mononeuritis multiplex.

• Pericarditis.¹⁸

• Peritonitis.

• Unlike polyarteritis nodosa, hypertension and eosinophilia are unusual.

Differential diagnosis¹⁹

Granulomatosis with polyangiitis is capable of mimicking numerous other diseases and it is the presence of two or more of the above signs and/or symptoms which must signal the possibility of the diagnosis.

Common conditions which enter the differential diagnosis include:

• Antiglomerular basement membrane (anti-GBM) antibody disease - a rare autoimmune condition in which antibodies are directed towards the glomerular basal membrane and alveoli.²⁰

• Legionella infection.

• Mixed connective tissue disease.

• Systemic lupus erythematosus.

• Other antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitides (ie microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis).

• Rheumatoid arthritis with systemic vasculitis.

• Mixed cryoglobulinaemia.

• Renal vein thrombosis with pulmonary embolism.

Investigations^{11 21}

• FBC, ESR.

• Serum U&Es.

• Blood test for cytoplasmic-ANCA (c-ANCA) with autoantibodies directed against proteinase 3 antibodies is seen in 80%-90% of the cases, and the remaining are perinuclear-ANCA (p-ANCA) directed against myeloperoxidase antibodies.²²

• Urinalysis for protein, blood and casts.

• Nasal endoscopy.

• Lung function tests and flow volume loop looking for subglottic stenosis.

• CXR looking for cavity formation and pulmonary infiltrates.

• Chest CT imaging to exclude lung parenchymal involvement.

• Sinus CT scan to exclude sinus disease.

• Biopsy of affected tissue, which may include nasal mucosa, lung biopsy, renal biopsy, looking for presence of vasculitis and granulomas.

Granulomatosis with polyangiitis treatment and management²³

Medical care

• Principles of care include rapid diagnosis, early induction of remission, maintenance of remission and prevention of drug toxicity.

• Investigations to exclude potentially life-threatening and/or vital organ damage should be instituted as a priority.

• Patients who are asymptomatic and have no organ damage may not need immunosuppressive treatment. Such patients should initially be offered methotrexate to induce remission (with mycophenolate mofetil as an alternative for those intolerant of methotrexate).

• Cyclophosphamide should be offered to promote remission in patients who have life-threatening and/or vital organ damage. Due to its serious adverse effects (for example, renal, haematological and neurological toxicity), it is normally given as pulsed treatment intravenously every 2-4 weeks. Long-term toxicity is dependent on lifetime cumulative dose which should be ≤25 g.

• Rituximab is recommended by the National Institute for Health and Care Excellence (NICE) if:²⁴

  • Further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose; or

  • Cyclophosphamide is contra-indicated or not tolerated; or

  • The person has not completed their family, and treatment with cyclophosphamide may materially affect their fertility; or

  • The disease has remained active or progressed despite a course of cyclophosphamide lasting 3-6 months; or

  • The person has had uroepithelial malignancy.

• Prednisolone is given in addition to cyclophosphamide or rituximab, as it helps to increase patient survival and suppress local disease.

• Aggressive immunosuppressive therapy is required to control pulmonary and renal involvement. Plasma exchange is sometimes used as an adjunct in these circumstances.

• Once the patient is in remission, cyclophosphamide should be replaced by azathioprine or methotrexate. Leflunomide or mycophenolate may be given as alternatives if there is intolerance or lack of efficacy.

• Once the patient has been in remission for at least a year, on maintenance therapy, prednisolone can be tapered off. If the patient remains in remission six months after this, immunosuppressive treatment can be withdrawn.

• Relapses should be treated by increasing prednisolone and optimising immunosuppressive therapy. Plasma exchange may be needed. Triggers for relapse (for example, infection, malignancy, change in drug therapy) should be considered.

• The treatment of refractory cases remains a challenge. Rituximab is more effective than cyclophosphamide in these circumstances. Triggers should be considered and the diagnosis reviewed.

• In 2022 NICE recommended avacopan with a cyclophosphamide or rituximab as an option for treating severe active granulomatosis with polyangiitis in adults.²⁵ Management with avacopan offers an effective and corticosteroid-free alternative to standard treatment.²⁶

Surgical care²⁷

Surgical treatment may be needed for:

• Nasal deformity.

• Subglottic stenosis.

• Obstruction of lacrimal ducts.

• Bronchial stenoses.

• Eustachian dysfunction (insertion of grommets).

• Acute kidney injury (renal transplant).

Complications¹¹

• Acute kidney injury.

• Respiratory failure.

• Chronic conjunctivitis.

• Nasal septum perforation.

Granulomatosis with polyangiitis prognosis

• GPA is associated with significant morbidity and mortality either due to irreversible organ dysfunction or due to the consequences of intensive/prolonged use of glucocorticoids and immunosuppressive agents. The average life expectancy for a patient with GPA without any treatment is 5 months, with a 1-year survival rate of less than 20%.²²

• Recently advances in treatment have improved the prognosis of patients with GPA, and more effective and less toxic treatment regimes have allowed them to lead a relatively normal life.²² The prognosis looks more optimistic - 80% of patients now achieve remission although relapses remain frequent (50% at eight years).²⁸

• There are refractory cases remaining resistant to treatment. A poor prognosis is thought to be related to deteriorating renal function and a situation in which the disease process is dominated by systemic vasculitis rather than granulomatosis.²⁹